The aim of this Program Project is to explore influences of genes and the environment on neuronal vulnerability to degeneration in aging and Alzheimer's disease (AD), thereby identifying potential translational therapies for humans with AD. The resubmission of this program project will both build upon progress from the previous period of funding, and explore new evidence that physical activity influences cognitive and cellular features of neural function. Each project focuses on these central themes while examining individual mechanisms and specific models in detail. Project 1 focuses on effects of Neuregulin 1 gene expression on AB load, neuronal structure, neurogenesis and behavior on a background of aging and amyloid mutations in mice. Project 2 tests the hypothesis that genetic approaches to modifying amyloid processing, including overexpression of amyloid-degrading enzymes, can improve neuronal structural, electrophysiology, neurogenesis and behavior in amyloid mutant mice. Project 3 examines the extent to which glutamatergic and nicotinic mechanisms influence amyloid processing, caspace activation, neural structure and neurogenesis. Project 4 tests the hypothesis that BDNF ameliorates neuronal dysfunction and death in primate models of entorhinal/hippocampal degeneration using methods clinically practical in AD, and explores whether augmented physical activity in aged primates improves neuronal structure, cognitive ability and neurogenesis. Core A will coordinate activities and administration of all projects and Cores, and provide statistical support. Core B, the Vector Core, will support the a variety of recombinant vector needs that constitute a common theme in all projects. Core C will provide anatomical and electrophysiological support in evaluating effects of interventions from all projects on neuronal structure, synaptic plasticity, neurogenesis and behavior. The interdependency of resources and skills between Projects/Cores, as well as our past success with this PPG, support the argument that the Program Project is the most efficient and cost-effective way to address these issues.